Psychotic genes or forgetful ones?
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Alzheimer Disease↗
Biomedical subjects
Simon Lovestone
Publications and source records attributed to Simon Lovestone.
Truncated apoE forms tangle-like structures in a neuronal cell line.
Apolipoprotein E is the predominant brain lipoprotein and polymorphic variation in the APOE gene the major genetic susceptibly factor for late onset Alzheimer's disease (AD). Recently it was reported that carboxyl-truncated ApoE fragments induce tangle-like structures in neurons. We confirm the finding: in mouse neuroblastoma cells truncated apoE fragments lacking the carboxyterminus induce structures that have the appearance of neurofibrillary tangles. However these tangles are not induced in non-neuronal cells even in the presence of co-expressed neurofilaments or tau. Further understanding of the basis of this cell specificity might add to understanding of the cell specificity of tangles in AD.
Alzheimer Disease↗
Full genome screen for Alzheimer disease: stage II analysis.
We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1).
Alzheimer Disease↗
The clinical phenotype of familial and sporadic late onset Alzheimer's disease.
BACKGROUND: Familial factors are clearly associated with an increased risk of developing late onset Alzheimer's disease (LOAD). However, there is emerging evidence to suggest that familial factors may also influence clinical phenotype. To date, most studies have focussed on familial influences upon age of onset or duration of illness and few studies have compared the frequency of non-cognitive symptoms between familial and sporadic LOAD. OBJECTIVE: To describe the clinical phenotype, with an emphasis on non-cognitive symptoms, of patients with LOAD and to explore familial differences. METHOD: 374 patients with LOAD were recruited from the community based Camberwell Dementia Case Register and a comparison made of the clinical phenotype of patients with and without a first degree family history of dementia. RESULTS: A first degree family history of dementia was found in 27% of fully ascertained cases. An earlier age of onset was found in familial cases (77.2 years compared to 78.3 years, p<0.05). However, no other differences in clinical phenotype, including the rate of cognitive decline, duration or the frequency of non-cognitive symptoms, were found between familial and sporadic cases. CONCLUSIONS: Apart from an earlier age of onset, patients with familial LOAD, as a group, do not have major differences in their clinical phenotype compared to patients with sporadic LOAD.
Age Factors↗
Out of sight out of mind? Support and information given to distant and near relatives of those with dementia.
OBJECTIVES: Increasing attention has been paid to the needs of family members caring for a person with dementia but little has been written about the impact on the wider family. This paper was intended to see whether the need for information would stretch to those relatives living far from the patient. METHOD: A case-control study comparing two sets of relatives of community-dwelling probands in contact with secondary services and having a clinical diagnosis of dementia: one set of relatives living less than an hour away and another set living further away.The reported need for and source of information obtained by relatives was questioned using a specially designed questionnaire. Mini Mental State Examination (MMSE) and Clinical Dementia Ratings Scale were used with probands. RESULTS: Relatives living distantly from the person with dementia reported similar rates of subjective distress but were more often dissatisfied with information received. Distant relatives were also less likely to access information from books or lay societies. CONCLUSION: The impact of having a relative with dementia does not lessen with distance. The wider family need support and information as well as 'primary carers'. If the whole family is to be supported in their caring role, then clinicians and the lay societies need to widen their supportive net.
Case-Control Studies↗
Alzheimer's disease-do tauists and baptists finally shake hands?
The amyloid cascade hypothesis has been the predominant model of molecular pathogenesis in Alzheimer's disease. The finding of tau mutations in other dementias has added weight to the hypothesis as it suggests that tau-pathology is a downstream but essential part of the dementing process. However, some observations remain difficult to reconcile with the hypothesis. In transgenic mice, for example, amyloid generation does not induce the predicted cascade and in man, plaques and tangles are separated temporally and spatially. One alternative possibility is that some common factor, loss of wnt signalling for example, might induce both plaques and tangles.
Alzheimer Disease↗
Genetics, molecular biology, neuropathology and phenotype of frontal lobe dementia: a case history.
BACKGROUND: Mutations in tau have been found in a group of related disorders including the frontal lobe dementias. AIMS: To describe the clinical features and molecular pathology changes in a single case of a patient with frontal lobe dementia. METHOD: A case report was compiled from neuropathological reports and genomic and gene expression analyses. RESULTS: A case with a splice-site mutation resulting in a typical frontotemporal clinical and neuropathological phenotype was found. Gene expression analysis suggests differential expression of isoforms of tau in regions in the brain. CONCLUSIONS; Frontotemporal dementia can result from gene mutations that alter splicing and expression of tau.
Dementia↗
Genes related to vascular disease (APOE, VLDL-R, DCP-1) and other vascular factors in late-life depression.
OBJECTIVE: The authors asked whether polymorphic variation at three genes related to vascular disease, and other vascular disease risk factors, determine late-life depression. METHODS: A group of 370 participants, representing 57% of survivors of an initial cohort of 1,083 participants in the Medical Research Council treatment trial of hypertension in older adults, had been screened for depression at baseline and were traced and genotyped for genetic analysis 11 years later. Genetic analyses were performed to establish variability at three polymorphisms related to vascular disease: APOE encoding for apolipoprotein-E, VLDL-R encoding for the VLDL cholesterol-receptor, and DCP-1 encoding for angiotensin-converter enzyme. Information on vascular disease and its risk factors (ECG ischemia or arrhythmia, body mass index, serum cholesterol, smoking status, and systolic/diastolic blood pressure) and cognitive functioning was also available from baseline. RESULTS: The authors found no association between the three studied polymorphisms and depression. Female gender, higher diastolic blood pressure, poorer cognitive functioning, and smoking status at baseline were all associated with depression independently of antidepressant and NSAIDs use, age, ECG-established vascular disease, and the remaining vascular disease risk factors studied. CONCLUSIONS: This study found no association between late-life depression and three polymorphisms related to vascular disease. Depression was found to independently associated with smoking, female gender, poorer cognitive functioning, and higher diastolic blood pressure. Taken together, this study does not seem to support the notion of a specific link between the studied vascular risk factors or these vascular-related loci and late-life depression.
Age of Onset↗